DERIVATIVES OF ACYL-PIPERAZINYL-PYRIMIDINE AND A PHARMACEUTICAL COMPOSITION THEREOF

Abstract

THE DERIVATIVES OF ACYL-PIPERAZINYAL OF GENERAL FORMULA (I) WHERE X IS O OR S R 1 IS ALKOXY OR TRIFLUOROMETHYL R 2 IS ALKYL CYCLOALKYL HETEROCYCLOALKYL, ARYL ARYLALKYS TETEROARYL OR HETEROARYLALKYL SHOW ACTIVITY IN THE CENTRAL NERVOOUS SYSTEM.COMPOUNDS OF GENERL FORMULA (1) IN WHICH X IS O CAN BE OBTAINEDE BY RRECTING A DERIVATIVE OF PYR4IMIDINE WITH A DERIVATIVE OF PIPERAZINE OR BY REACTING A DERIVATIV OF IPERAZINYLPYRIMIDINE WITH A CARBOXYLIC ACID OR A SALT OR DERIVATIVE THEREOF. COMPOUND OF GENERAL FORMULA (1) IN WHICH X IS S CAN BE OBTAINED BY REACTING (1) IN WHICH X IS O WITH LLAWESSONS REAGENT OR WOTH PHOSPHOROUS PENTASULPHIDE. THE COMPOUNDS (1) SHOW SEDATIVE ACTIVITY, ANTICONVULSANT SLEEP- INDUCING OR GENERAL ANAESTHETIC AND CAN BE APPLIED IN JUMAN OR VERINARY MEDICINE.

Full Text

FIELD OF THE INVENTION
The present invention relates to new acyl-piperazinyl-pyrimidines of the general
formula (I), to their physiologically acceptable salts, to procedures for their preparation,
to their application as medicaments in therapy for humans and/or as veterinary
medicaments and to the pharmaceutical compositions which contain said compounds.
The new compounds object of the present invention can be used in the
pharmaceutical industry as intermediates and for the preparation of medicaments.
BACKGROUND OF THE INVENTION
In our patents EP 382 637 and EP 497 659 we have described different
derivatives of alkyl-piperazinyl-pyrimidines of the general formula (II) with ansiolytic and
or tranquillising properties.
We have now discovered that the addition of a substituent to position 4 of the
pyrimide and the substitution of an alkyl radical with an acyl radical gives rise to the new
compounds of general formula (I). Said compounds show useful biological properties
which makes them especially useful for their use in therapy in humans and veterinary
therapy. The compounds of the present invention are useful as agents which act on the
central nervous system in mammals including humans. In particular, the new compounds
are useful as sedatives, anti-convulsants, sleep-inducing agents and general anaesthetics.
ACCOMPANYING
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the results of the sedative activity of some of the compounds of
the invention, as determined by reduction in locomotive activity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new compounds capable of inducing conscious
sedation, of acting as sleep-inducing agents, anti-convulsants, analgesics, muscular
relaxants, anti-tusigenics, ansiolytics, anti-psychotics, anti-depressants, anti-cerebral
ischeamics, anti-migraine agents, agents useful for sleep disorders, agents for
neurodegenerative diseases, agents for cognitive disorders and Alzheimer"s disease, and
agents capable of inducing or maintaining general anaesthesia, when administered by an
appropriate method at a suitable dosage level.
The compounds of the present invention are represented by the general formula
(I)
where
X is an oxygen or sulphur atom;
R1 is a C1-4 alkoxy or trifluoromethyl radical;
R2 is a C1-6 alkyl radical; C3-6 saturated cycloalkyl; heterocycloalkyl
consisting of a ring of 3 to 6 atoms in which the heteroatom is selected from an atom of
oxygen, sulphur or nitrogen, optionally N-substituted; phenyl optionally substituted with
1, 2 or 3 identical or different substituents selected from fluorine, chlorine, bromine,
amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl consisting of a
C1-3 alkyl group substituted by a phenyl radical optionally substituted by 1, 2 or 3
identical or different substituents selected from fluorine, chlorine, bromo, amino,
acetamido, nitro, methyl, trifluoromethyl and methoxy; heteroaryl consisting of a 5 or 6
heteroatom ring, optionally substituted, or of fused heteroaromatic systems optionally
substituted, of 9 or 10 atoms consisting of 1 or 2 heteroatoms selected from oxygen,
sulphur and nitrogen, selecting the aforementioned substituents from flourine, chlorine,
bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and
heteroarylalkyl consisting of an alkyl group of 1 to 3 carbon atmos substituted with a
heteroaryl radical consisting of a 5 or 6 member heteroaromatic ring, optionally
substituted, or of fused 9 to 10 member heteroaromatic systems, optionally substituted
with 1 or 2 heteroatoms selected from oxygen, sulphur and nitrogen, selected the
aforementioned substituents from fluorine, chlorine, bromine, amino, acetamido, nitro,
methyl, trifluoromethyl and methoxy; and their physiologically acceptable salts.
The present invention also provides a pharmaceutical composition characterised in
that it contains, in addition to a pharmaceutically acceptable excipient, at least one
compound of general formula (I) or one of its physiologically acceptable salts.
In the present invention, the term C1-4 "alkoxy" represents a radical OR3 in which
R3 is a saturated linear or branched carbon chain containing 1 to 4 atoms, such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy o tert-butoxy for example.
The term "alkyl" represents a radical derived from a saturated linear or branched
hydrocarbon. The term C1-6 alkyl represents a linear or branched chain alkyl radical
containing 1 to 6 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl for example.
The term C3-6 saturated "cycloalkyl" represents a saturated ring of 3 to 6 atoms of
carbon, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl for example.
The term "heterocycloalkyl" represents a ring of 3 to 6 atoms of which there is a
heteroatom such as an oxygen atom or an atom of sulphur, such as a 2-aziridinyl, 2-
tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl for example,
or an atom of nitrogen which may or may not be substituted, such as 2-azetidinyl, 2-
piperidinyl, 3-piperidinyl or 4-piperidinyl for example.
The term "aryl" represents an unsubstituted or substituted phenyl radical, with 1,
2 or 3 identical or different substituents such as fluorine, chlorine, bromine, amino,
acetamido, nitro, methyl, triflouromethyl or methoxy, such as 2-fluorophenyl, 3-
fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-
bromophenyl, 3-bromorophenyl, 4-bromophenyl, 2-aminophenyl, 3-aminophenyl, 4-
aminophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitophenyl, 2-acetamidophenyl, 3-
acetamidophenyf, 4-acetamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-
methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-(trifluoromethyl)phenyl, 3-
(trifluorpmethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-metoxyphenyl, 3-metoxyphenyl, 4-
metoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,3-
dibromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-
dimethylphenyl, 2,4-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-
dimethoxyphenyl for example.
The term "arylalkyl" represents a linear or branched chain of 1 to 3 atoms of
carbon which is substituted with an aryl radical, according to the hereinbefore definition
of "aryl", and which includes substituents such as phenylmethyl, 1-phenylethyl, 2-
phenylethyl, 3-phenylethyl, 3-phenylpropyl, as well as other radicals in which the
aromatic ring is substituted with groups such as fluorine, chlorine, bromine, amino,
acetamido, nitro, methyl, trifluoromethyl or methoxy.
The term "heteroaryl" represents a substituted or unsubstituted heteraromatic
ring of 5 or 6 members or unsubstituted or substituted fused heteroaromatic systems of 9
or 10 members consisting of 1 or 2 heteroatoms such as nitrogen, oxygen or sulphur,
with the substituent groups being groups such as fluorine, chlorine, bromine, amino,
acetamido, nitro, methyl, trifluoromethyl or methoxy, such as 2-furyl, 3-furyl, 2-thienyl,
3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 3-methoxy-2-thienyl, 3-chloro-2-
thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
indolyl, 3-indolyl, 2-benzo[b]thienyl, 3-benzyo[b]thienyl, 3-chloro-2-benzo[b]thienyl,
pirazolyl, imidazolyl, pyrimidinyl, piridazinyl, pirazinyl, benzimidazolyl, quinolyl,
oxazolyl and thiazolyl for example.
The term "heteroarylalkyl" represents an alkyl group of 1 to 3 atoms of carbon
which is substituted with a heteroaryl radical, according to the hereinbefore definition of
"heteroaryl", and which includes substituents such as 2-thienylmethyl, 2-
benzo[b]thienylmethyl and 3-(4-chloropyrazolyl)propyl.
The new compounds of general formula (I) may contain an asymmetric carbon
atom and can therefore be prepared as optical isomers or racemates. The racemates of
compounds (I) can be resolved into their optical isomers using conventional methods,
such as separation by chiral chromatography or fractionated crystallisation from their
diasteroisomer salts for example. Similarly, they can also be obtained from asymmetric
synthesis using chiral precursors.
The present invention also relates to physiologicaly acceptable salts of the
compounds of general formula (I), in particular addition salts of mineral acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid and
addition salts of organic acids such as p-toluensulphonic acid or methansulphonic acid.
The new derivatives of general formula (I), in which X is an atom of oxygen and
R1 and R2 have the hereinbefore defined meaning, can be prepared according to methods
A or B which are described below.
METHOD A:
The compounds of general formula (I) can be prepared by reacting the derivative
of chloropyrimidine (III), where R1 has the hereinbefore defined meaning, with a
derivative of piperazine of general formula (IV) in which X and R2 have the hereinbefore
defined meaning.
The reaction is carried out in an organic solvent, for example in an chlorinated
hydrocarbon such as dichloromethane or chloroform, a linear or cyclic ether such as 1,2-
dimethoxyethane, tetrahydrofurane or dioxane, a aprotic polar solvent such as pyridine,
dimethylsulphoxide or dimethylformamide or any other type of solvent appropriate for
carry out a aromatic nucleophilic substitution reaction. The reaction can be carried out
in the presence of a mineral or organic base such as an aliphatic amine, preferably
triethylamine or M-methylmorphine by stirring at a temperature lying between room
temperature and the boiling point of the solvent for a period of time lying between ten
minutes and twenty-four hours, the preferring conditions being a period of time between
thirty minutes and five hours.
METHOD B:
By reaction of the amine of formula (V):
in which R1 has the hereinbefore defined meaning with a carboxylic acid of the general
formula R2COOH (VI), in which R2 has the hereinbefore defined meaning, or with a salt
of said acid or also with a derivative reagent R2COY (VII).
Examples of salts include salts of alkali metals such as sodium salts and
potassium salts, alkaline earth salts such as calcium salts and magnesium salts,
ammonium salts, and salts of organic bases such as triethylamine, trimethylamine,
pyridine and picoline.
Examples of derivative reagents of general formula R2COY (VII) in which Y is a
halogen atom preferably a chlorine atom or a bromine atom, an azide group (-N3), a 1-
imidazolyl, a O-CO-R4, in which R4 can be an alkyl or aryl radical of 1 to 6 carbon
atoms, preferably substituted with one or several halogen atoms, or a group OR5 where
R5 represents an aromatic group of one or. two rings substituted with one or several
halogen atoms or nitro radicals, the preferred groups being 4-nitrophenyl, 2,4-
dinitrophenyl, pentachlofophenyl, pentafluorophenyl, 1-benzotriazolyl o N-succinimide.
Similarly, instead of using the aforementioned derivative reagents, compounds of general
formula (I) can be prepared directly by reaction of the amine (V) with the carboxylic acid
or general formula (VI). In this case it is preferable that the reaction proceeds in the
presence of reagents that activate the carbonyl groups such as N,N"-
dicyclohexylcarbodiimide, diisopropylcarbondiimide or 3-(3-dimethylamino)propyl-l-
ethycarbodiimide. This reaction can also be carried out using the said carbodiimidas in
the presence of 1-benzotriazol or N-hydroxysuccinimide. The acids of general formula
(VI) and the amine of formula (V) also react directly in the presence of N,N"-
carbonyldiimidazol or of propanophosphonic acid anhydride.
The reaction is carried out in an organic solvent, for example in an
chlorinated hydrocarbon such as dichloromethane or chloroform, a linear or cyclic ether
such as 1,2-dimethoxyethane, tetrahydrofurane or dioxane, a aprotic polar solvent such
as pyridine, dimethylsulphoxide or dimethylformamide or any other type of solvent
appropriate for carry out a aromatic nucleophilic substitution reaction. The reaction can
be carried out in the presence of a mineral or organic base such as an aliphatic amine,
preferably triethylamine or M-methylmorphine by stirring at a temperature lying between
room temperature and the boiling point of the solvent for a period of time lying between
ten minutes and twenty-four hours, the preferring conditions being a period of time
between thirty minutes and five hours.
METHOD C
The new derivatives of general formula (I), in which X is an atom of sulphur and
R1 and R2 have the hereinbefore defined meaning, can be prepared according to the
following method.
By treating a compound of a compound of general formula (I), in which R1 and
R2 have the hereinbefore defined meaning and in which X is an atom of oxygen, with
Lawesson"s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphaethano-2,4-
disulphuro) or with phosphorous pentasulphide, the corresponding thioamides are
obtained in which X is a sulphur atom:
The reaction is carried out in an organic solvent such as toluene, benzene,
heptane, pyridine or tetrahydrofurane. The reaction is continually shaken at a
temperature lying between room temperature and the boiling point of the solvent for a
period of time of between one hour and twenty-four hours, preferably carrying out the
reaction at 80°C for a time between one hour and sixteen hours.
METHOD D:
The salts of the compounds of general formula (I) can be prepared by reaction
with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid,
sulphuric acid, nitric acid or with an organic acid such as p-toluensulphonic acid or
methansuiphonic acid in an appropriate solvent such as methanol, ethanol, ethyl ether,
ethyl acetate, acetonitrile or acetone, being obtained with the normal precipitation
techniques or crystallisation of the corresponding salts.
The invention provides pharmaceutical compositions which comprise, as well as a
pharmaceutically acceptable excipient, at least one compound of general formula (I) or
one of their physiologically acceptable salts. The invention also relates to the use of a
compound of general formula (I) and their physiologically acceptable salts in the
elaboration of a medicament with activity in the mammalian, central nervous system,
including activity in the human central nervous system in particular, in the manufacture of
a medicament with sedative, anticonvulsive, sleep-inducing and general anaesthetic
activity.
In the examples which follow the preparation of new compounds according to
the invention is indicated. Also described are some typical forms of use for the different
fields of application, as well as medicinal formulas applicable to the compounds of the
invention.
METHOD A:
Example 1. Preparation of 2-[4-(2-furvlcarbonvD-l-piperazinvl1-4-methoxv-
pvrimidine.
A solution of 1.0 g (6.92 mmol) of 2-chloro-4-methoxypyrimidine, 1.49 g (8,30 mmol)
of l-(2-furylcarbonyl)piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 mL of n-
butanol is maintained under gentle reflux conditions overnight. The solvent is
evaporated off under reduced pressure and the crude residue is diluted in chloroform and
washed in water. The organic phase is dried over NaSO4 and evaporated to dryness to
give a crude product which is purified using silica-gel chromatography eluting with ethyl
acetate/petroleum ether 70:30 to yield an oil which solidifies when left to stand. The
solid is suspended in petroleum ether to yield 1.4 g (4.86 mmol) of 2-[4-(2-
furylcarbonyl)-l-piperazinyl]-4-methoxypyrimidine. m.p. = 85-86°C.
METHOD B:
Example 3. Preparation of 4-methoxy-2-"4-(2-thienylcarbonyl)-1-piperazinyl]
pyrimidine
A solution of 1.0 g (5.15 mmol) of 4-methoxy-2-(l-piperazinyl)pyrimidine and 1 mL
(7.18 mmol) of triethylamine in 30 mL of CH2Cl2 is cooled to 0° C and 0.76 g (5.18
mmol) of 2-thienylcarbonyl chloride slowly added. The solution is kept at 0° C for an
hour and then the temperature allowed to rise to room temperature. The organic phase
is washed with H2O, dried over NaSO4 and the solvent removed under reduced pressure.
The crude residue is dissolved in ethyl ether crystallising 1:0 g (3.28 mmol) of 4-
methoxy-2-[4-(2-thiencarbonyl)-l-piperazinyl]pryimidine. m.p. = 71-73° C
Example 12. Preparation of 4-methoxy-2-[4-(3-thienylcarbonyl)-l-piperazinyl]
pyrimidine.
To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 mL (7.86 mmol) of
triethylamine in 30 mL of CH2Cl2 cooled to 0° C 0.84 g (7.81 mmol) of ethyl
chloroformiate are added. The mixture is maintained at 0° C for 20 minutes and then 1.5
g (7.81. mmol) of 4-methoxy-2-(l-piperazinyl) pyrimidine dissolved in 10 mL of CH2Cl2
are added to the solution. The temperature is allowed to rise to room temperature and
the solution continually stirred for 2 hours and the organic phase is washed with H2O,
dried over NaSO4 and the solvent evaporated off under reduced pressure. The resulting
oil is treated with ethyl ether to yield a solid which is recrystallised from ethanol/H2O to
give 0.8 g (2.63 mmol) of 4-methoxy-2-[4-(3-thienylcarbonyl)-l-piperazinyl]pyrimidine.
m.p. = 90-92° C.
Example 20. Preparation of 2-[4-(2-inolylcarbonyl)-1-piperazinyl]-4-methoxy
pvrimidine.
To a solution of 0.83 g (5.15 mmol) of indol-2-carboxylic acid in 15 mL of dry THF 0.83
g (5.15 mmol) of N,N"-carbonyldiimidazol is added. After 30 minutes 1.0 g (5.15 mmol)
of 4 methoxy-2-(l-piperazinyl) pyrimidine is added to the solution and it is left overnight
with continuous stirring. The solvent is eliminated under reduced pressure and H2O
added. This produces a precipitate which is filtered and dried, to give 1.7 g (5.04 mmol)
of 2-[4-(2-indorylcarbonyl)-l-piperazinyl]-4-methoxypyrimidine. m.p. = 202-203° C.
METHOD C
Example 54. Preparation of 4-methoxy-2-(4-thiobenzoyl-l-piperazinyl) pyrimidine.
0.56 g (1.9 mmol) of 2-(4-benzoyl-l-piperazinyl)-4-methoxypyrimidine are dissolved in
25 mL of dry toluene, and 0.46 g (1.14 mmol) of Lawesson"s reagent (2,4-bis(4-
methoxyphenyl)-l,32,4-dithiadiphosphaethano-2,4-disulphide) added. The mixture is
heated to 80-90° C for 16 hours. Ethyl ether is added, basic water is used to wash the
residue and the organic extract is dried with NaSO4 and the solvent evaporated off under
reduced pressure. The resulting crude residue is crystallised with ethyl ether-petroleum
ether to give 160 mg (0.5 mmol) of 2-(4-thiobenzoyl-l-piperazinyl)-4-
methoxypyrimidine. m.p. = 125-129° C.
METHOD D:
Example 2. Preparation of 2-[4-(2-furylcarbonyl)-1 -piperazinyl]-4-methoxypyrimidine
chlorohydrate.
1.0 g (3.47 mmol) of 2-[4-(2-furylcarbonyl)-l-piperazinyl]-4-methoxypyrimidine in ethyl
acetate and a few drops of a solution of ethyl ether/hydrochloric acid are added, thus
obtaining a precipitate which is filtered and dried, to yield 1.07 g (3.29 mmol) of 2-[4-(2-
furylcarbonyl)-l-piperazinyl]-4-methoxypyrimidine chlorohydrate. m.p. = 162-164° C.
Example 4. Preparation of 4-methoxy-2-[4-(2-thienylcarbonyl)-1-piperazinyl]
pyrimidine chlorohydrate.
1.0 g (3.29 mmol) of 4-methoxy-2-[4-(2-thienylcarbonyl)-l-piperazinyl] pyrimidine is
dissolved in acetone and a few drops of a solution of ethyl ether/hydrochloric acid are
added, thus obtaining a precipitate which is filtered and dried, to yield 1.05 g (3.08
mmol) of 4-methoxy-2-[4-(2-thienylcarbonyl)-l-piperazinyl] pyrimidine chlorohydrate.
m.p. = 143-145° C.
Example 13. Preparation of 4-methoxy-2-[4-(3-thienvlcarbonyl)-l-piperazinyl]
pyrimidine chlorohydrate.
0.8 g (2.63 mmol) of 4-methoxy-2-[4-(3-thienylcarbonyl)-l-piperazinyl] pyrimidine is
dissolved in ethanol and a few drops of a solution of ethanol/hydrochloric acid are added,
thus obtaining a precipitate which is filtered and dried, to yield 0.6 g (1.76 mmol) of 4-
methoxy-2-[4-(3-thienylcarbonyl)-l-piperazinyl] pyrimidine chlorohydrate. m.p. = 154-
156° C.
Sleep-inducing activity in mice
The sleep-inducing activity of the products of the present invention have been
studied, evaluating the their capacity to increase the sleep time induced by barbital,
according to a modification of the method described by David Sudgen (J. Pharmacol.
Exp. Ther., 1983, 227, 3).
Fifteen minutes after the administration of barbital (150 mg/Kg, i.v.), the mice
were treated with the product of the study at an initial dose of 100 mg/Kg (i.p.). For the
most active products a dosage efficacy 50 (DE50) was determined. The results for some
of the products of the invention are shown in Table 2, taking meprobamate as the
reference product.
General anaesthetic activity
The general anaesthetic activity was study in mice, injecting the product of the
study in the caudal vein. The start and duration time of sleep were recorded. The results
for some of the products of the patent are shown in Table 3 and it can be seen that they
show a clear anaesthetic activity with respect to the reference compound (Propofol),
with the animals recovering later.
Sedative activity
The sedative activity of some of the products on the locomotive activity of mice
at different dosages has been studied. The technique described by T.G. Heffheren J.
Pharm. Exp. Ther., 1989, 251, 105-112 has been followed. The measurement of the
locomotive activity is carried out by dividing the rats into groups of four and determining
the movement of the animals in an automated fashion using a video installation and the
SMART program (Letica S.A.) for image analysis. The measurement of activity started
5 minutes after the administration of the product via i.p. and continued for twenty
minutes. The results (Figure 1) show the sedative effect of the compounds tested.
Muscular relaxant activity
The muscular relaxant activity has been studied in the products of the invention
by evaluated their effect on the abdominal body tone of mice, following the method
described by S. IRWING (Gordon Res. Conf. On Medicinal Chem., 1959, p. 133).
The mice received the products under study at a dosage of 80 mg/kg, via I.p.,
and at different times after administration (1/2, 1, 2, 3, 4 and 5 hours) the body tone and
the abdominal tone was evaluated looking at the muscular tension compared to the
control animals.
The results listed in Table 4 show that many of the products are noticeably active
as muscular relaxants. This effect lasts longer than for propofol or zolpidem, which were
used as reference products.
Table 4 Miorelaxant activity in the Trwing mouse test.
[Dosage = 80 mg/kg, i.p.]
Analgesic activity
The analgesic activity of the products of the invention have been studied by
evaluation of their effect in the test of contortions induced by phenylbenzoquinone in
mice, following the method described by Siegmund E., and coworkers (Proc. Soc. Exp.
Biol. Med. 1957, 95: 729-731).
The mice received the products of the study, a different dosage levels, and one
hour later they received an injections i.p. of 5 mg/kg of phenylbenzoquinone. The
contortions of the mice were registered for the following fifteen minutes and compared
with the contortions of the control group. The DE50 (dosage efficacy 50) of the
compound of Example 4 is shown. This compound showed a better analgesic activity
than aspirin, both when administered subcutaneously and orally.
Table 5. Analgesic activity. Protection from contortions induced by
phenylbenzoquinone in mice.
WE CLAIM:
1. Derivative of acyl-piperazinyl-pyrimidine of general formula (I)
where
X is an oxygen or sulphur atom;
R1 is a C1-4 alkoxy or trifluoromethyl radical;
R2 is a C1-6 alkyl radical; C3-6 saturated cycloalkyl; heterocycloalkyl
consisting of a ring of 3 to 6 atoms in which the heteroatom is selected from an atom of
oxygen, sulphur or nitrogen, optionally N-substituted; phenyl optionally substituted with
1, 2 or 3 identical or different substituents selectred from fluorine, chlorine, bromine,
amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl consisting of a
C1-3 alkyl group substituted by a phenyl radical optionally substituted by 1, 2 or 3
identical or different substituents selected from fluorine, chlorine, bromo, amino,
acetamido, nitro, methyl, trifluoromethyl and methoxy; heteroaryl consisting of a 5 or 6
heteroatom ring, optionally substituted, or of fused heteroaromatic systems optionally
substituted, of 9 or 10 atoms consisting of 1 or 2 heteroatoms selected from oxygen,
sulphur and nitrogen, selecting the aforementioned substituents from flourine, chlorine,
bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and
heteroarylalkyl consisting of an alkyl group of 1 to 3 carbon atmos substituted with a
heteroaryl radical consisting of a 5 or 6 member heteroaromatic ring, optionally
substituted, or of fused 9 to 10 member heteroaromatic systems, optionally substituted
with 1 or 2 heteroatoms selected from oxygen, sulphur and nitrogen, selected the
aforementioned substituents from fluorine, chlorine, bromine, amino, acetamido, nitro,
methyl, trifluoromethyl and methoxy; and their physiologically acceptable salts.
2. A compound as claimed in claim 1, in which R1 is methoxy, ethoxy, propoxy,
isopropoxy, butoxy, sec-butoxy or tert-butoxy.
3. A compound as claimed in claim 1, in which R2 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.
4. A compound as claimed in claim 1, in which R2 is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl.
5. A compound as claimed in claim 1, in which R2 is 2-azyridinyl, 2-tetrahydrofuryl,
3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-azetidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl.
6. A compound as claimed in claim 1, in which R2 is 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-clorophenyl, 3-clorophenyl, 4-clorophenyl, 2-bromophenyl, 3-
bromophenyl, 4-bromophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-
nitr
ophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-
acetamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 3-
methylphenyl, 4-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-
(trifluoromethyl)phenyl, 2-metoxyphenyl, 3-metoxyphenyl, 4-metoxyphertyl, 2,3-
difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,3-dibromophenyl, 3,4-
dibromophenyl, 2,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 2,4-
dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl.
7. A compound as claimed in claim 1, in which R2 is phenylmethyl, 1-phenylethyl, 2-
phenylethyl, 3-phenylpropyl, optionally substituted at the aromatic ring.
8. A compound as claimed in claim 1, in which R2 is 2-furyl, 3-furyl, 2-thienyl, 3-
thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 3-methoxy-2-thienyl, 3-chloro-2-thienyl,
5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-indolyl, 3-
indolyl, 2-benzo[b]thienyl, 3-benzyo[b]thienyl, 3-chloro-2-benzo[b]thienyl, pirazolyl,
imidazolyl, pyrimidinyl, piridazinyl, pirazinyl, benzimidazolyl, quinolyl, oxazolyl or
thiazolyl
9. A compound as claimed in claim 1, in which R2 is 2-thienylmethyl, 2-
benzo[b]thienmethyl or 3-(4-chloropirazolyl)propyl.
10. A compound as claimed in claim 1, selected from the following group:
• 2-[4-(2-furylcarbonyl)-1 -piperazinyl]-4-methoxypirimidine,
• 2-[4-(2-fiirylcarbonyl)-1 -piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 4-methoxy-2-[4-(2-thienylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(2-thienylcarbonyl)-1-piperazinyl]pyrimidine chlorohydrate,
• 2-(4-acetyl-1 -piperazinyl)-4-methoxypyrimidine,
• 2- {4-[4-(4-chloropyrazolyl)butanoyl]-1-piperazinyl}-4-methoxypyrimidine,
• 2- {4-[4-(4-chloropyrazolyl)butanoyl]-1-piperazinyl}-4-methoxypyrimidine
chlorohydrate,
• 2-(4-benzoyl-1 -piperazinyl)-4-methoxypyrimidine,
• 2-(4-cyclopropylcarbonyl-1-piperazinyl)-4-methoxypyrimidine,
• 2-[4-(2-furylcarbonyl)-1-piperazinyl]-4-(trifluoromethyl)pyrimidine,
• 2-[4-(2-thienylcarbonyl)-l-piperazinyl]-4-(trifluoromethyl)pyrimidine,
• 4-methoxy-2-[4-(3-thienylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(3 -thienylcarbonyl)-1-piperazinyl]pyrimidine chlorohydrate,
• 2-[4-(5-methyl-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(5-methyl-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine
chlroohydrate,
• 4-methoxy-2-[4-(3-methoxy-2-thienylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(3 -methoxy-2-thienylcarbonyl)-1-piperazinyl]pyrimidine
chlorohydrate,
• 2-[4-(2-benzo[b]thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-benzo[b]thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine
chlorohydrate,
• 2-[4-(2-indolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-chloro-2-benzo[b]thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-chloro-2-benzo[b]thienylcarbonyl)-1-piperazinyl]-4-methpxypyrimidine
chlorohydrate,
• 4-methoxy-2-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(2-pyrrolylcarbonyl)-1-piperazihyl]pyrimidine chlorohydrate,
• 4-methoxy-2-[4-(2-thienylacetyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(2-thienylacetyl)-1-piperazinyl] pyrimidine chlorohydrate,
• 2-[4-(3-methyl-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-methyl-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine
clorohydrate,
• 2-[4-(3-chloro-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-chloro-2-thienylcarbonyl)-l-piperazinyl]-4-methoxypyrimidine
chlorohydrate,
• 2-[4-(3-indolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-benzo[b]thienylacetyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(5-chloro-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(5-chloro-2-thienylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine
chlorohydrate,
• 4-methoxy-2-[4-(4-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 4-methoxy-2-[4-(4-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine
chlorohydrate,
• 2-[4-(4-fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(4-fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-[4-(4-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(4-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 4-methoxy-2-[4-(3-methoxybenzoyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(3-methoxybenzoyl)-1-piperazinyl]pyrimidine chlorohydrate,
• 2-[4-(3 -fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3 -fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-[4-(3-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3-chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 4-methoxy-2-[4-(2-methoxybenzoyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-[4-(2-methoxybenzoyl)-1-piperazinyl]pyrimidine chlorohydrate,
• 2-[4-(2-(fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-(fluorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-[4-(2-(chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-(chlorobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 4-methoxy-2-[4-(2-tetrahydrofurylcarbonyl)-1-piperazinyl] pyrimidine,
• 4-methoxy-2-(4-thiobenzoyl-1-piperazinyl)pyrimidine,
• 4-methoxy-2-[4-(2-tetrahydrofurylcarbonyl)-1-piperazinyl]pyrimidine
chlorohydrate,
• 4-methoxy-2-(4-thiobenzoyl-1-piperazinyl)pyrimidine chlorohydrate,
• 2-(4-benzoyl-1-piperazinyl)-4-methoxypyrimidine,
• 4-methoxy-2- {4-[4-(trifluoromethyl)benzoyl]-1-piperazinyl} pyrimidine,
• 4-methoxy-2-{4-[4-(trifluoromethyl)benzoyl]-l-piperazinyl}pyrimidine
chlorohydrate,
• 4-methoxy-2- {4-[3 -(trifluoromethyl)benzoyl]-1 -piperazinyl} pyrimidine,
• 4-methoxy-2-{ 4-[3-(trifluoromethyl)benzoyl]-1 -piperazinyl }pyrimidine
chlorohydrate,
• 4-methoxy-2- {4-[2-(trifluoromethyl)benzoyl]-1 -piperazinyl} pyrimidine,
• 4-methoxy-2- {4-[2-(trifluoromethyl)benzoyl]-1 -piperazinyl} pyrimidine
chlorohydrate,
• 4-methoxy-2-(4-nicotinoyl-1-piperazinyl)pyrimidine,
• 4-methoxy-2-(4-nicotinoyl-1-piperazinyl)pyrimidine dichlorohydrate,
• 2-(4-isonicotinoyl-l-piperazinyl)-4-methoxypyrimidine,
• 2-(4-isonicotinoyl-1-piperazinyl)-4-methoxypyrimidine dichlorohydrate,
• 2-[4-(l-imidazolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(l-imidazolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-(4-nicotinoyl-1-piperazinyl)-4-(trifluoromethyl)pyrimidine,
• 2-(4-nicotinoyl-1-piperazinyl)-4-(trifluoromethyl)pyrimidine chlorohydrate,
• 4-methoxy-2-`4-(2-pyridylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-methoxy-2-" 4-(2-pyridylcarbonyl)-1-piperazinyl]pyrimidine dichlorohydrate,
• 4-ethoxy-2-[4-(2-thienylcarbonyl)-1-piperazinyl]pyrimidine,
• 4-ethoxy-2-[4-(2-thienylcarbonyl)-1-piperazinyl]pyrimidine chlorohydrate,
• 2-[4-(3-chloro-2-thienylcarbonyl)-1-piperazinyl]-4-ethoxypyrimidine,
• 2-[4-(3-chloro-2-thienylcarbonyl)-1-piperazinyl]-4-ethoxypyrimidine
chlorohydrate,
• 4-ethoxy-2-{4-[2-(trifluoromethyl)benzoyl]-1-piperazinyl} pyrimidine,
• 4-ethoxy-2-{4-[2-(trifluoromethyl)benzoyl]-1-piperazinyl} pyrimidine
chlorohydrate,
• 2-[4-(2-methylbenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-methylbenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-[4-(4-fluorobenzoyl)-1-piperazinyl]-4-isopropoxypyrimidine,
• 2-[4-(4-fluorobenzoyl)-1-piperazinyl]-4-isopropoxypyrimidine chlorohydrate,
• 4-isopropoxy-2-{4-[2-(trifluoromethyl)benzoyl]-l-piperazinyl]pyrimidine,
• 4-isopropoxy-2- {4-[2-(trifluoromethyl)benzoyl]-1-piperazinyl]pyrimidine
chlorohydrate,
• 2-[4-(3-chloro-2-thiencarbonyl)-1-piperazinyl]-4-isopropoxypyrimidine,
• 2-[4-(3-chloro-2-thiencarbonyl)-1-piperazinyl]-4-isopropoxypyrimidine
chlorohydrate
• 2-[4-(cyclohexylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(cyclohexylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 4-ethoxy-2[4-(4-fluorobenzoyl]-1-piperazinyl} pyrimidine,
• 4-ethoxy-2[4-(4-fluorobenzoyl]-1-piperazinyl} pyrimidine chlorohydrate,
• 2-[4-(2-thiazolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-aminobenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-aminobenzoyl)-1-piperazinyl]-4-methoxypyrimidine chlorohydrate,
• 2-[4-(3-fluoro-2-thieylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(3 -fluoro-2-thieylcarbonyl)-1-piperazinyl] -4-methoxypyrimidine
chlorohydrate,
• • 2-[4-(4-methoxy-2-pyrimidinyl)-1-piperazinylcarbonyl]benzoic acid,
• 2-[4-(2-acetoxybenzoyl)-1-piperazinyl]-4-methoxypyrimidine,
• 2-[4-(2-hydroxybenzoyI)-1-piperazinyl]-4-methoxypyrimidine,
• sodium 2-[4-(4-methoxy-2-pyrimidinyl)-l-piperazinylcarbonyl]benzoate,
• 2-[4-(2-hydroxybenzoyI)-1-piperazinyl]-4-methoxypyrimidine hydrochlorate,
• 4-methoxy-2-[4-(2-methoxybenzoyl)-1-piperazinyl]-4-methoxypyrimidine, and
• 4-ethoxy-2[4-(2-pyridylcarbonyl]-l-piperazinyl}pyrimidine.
11. A pharmaceutical composition characterised in that it contains, in addition to a
pharmaceutically acceptable excipient, at least one compound of general formula (I) or
one of its physiologically acceptable salts, as claimed in claims 1 to 10.
12. The pharmaceutical composition as claimed in claim 1 to 10, wherein said
composition is useful in the treatment of disorders of central nervous system of
mammals including men.
13. The pharmaceutical composition as claimed in claim 1 to 10, wherein said
composition is useful as sedative, anticonvulsants, analgesic, muscular relaxant,
antitusigenic, ansiolytic, antipsicotic, antidepressant, anti-cerebral ischeamic, anti-
migraine activity, in the fabrication of a medicament for treating sleep disorders,
neurodegenerative diseases, cognitive disorders and Alzheimer"s disease, sleep-
inducing or general anaesthetic agents, for mammals, including men.
14. Derivatives of acyl-piperazinyl-pyrimidine,
substantially as herein described, particularly with
reference to the foregoing examples and as illustrated in the
accompanying drawing.
15. A pharmaceutical composition, substantially as herein
described, particularly with reference to the foregoing
examples and as illustrated in the accompanying drawing.
The derivatives of acyl-piperazinyl-pyrimidines of general formula (I), where X is O or S;
R1 is alkoxy or trifluoromethyl; R2 is alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, show activity in the central nervous system. Compounds
of general formula (I) in which X is O can be obtained by reacting a derivative of
pyrimidine with a derivative of piperazine or by reacting a derivative of iperazinyl-
pyrimidine with a carboxylic acid or a salt or derivative thereof. Compounds of general
formula (I) in which X is S can be obtained by reacting (I) in which X is O with
Lawesson"s reagent or with phosphorous pentasulphide. The compounds (I) show
sedative activity, anticonvulsant, sleep-inducing or general anaesthetic activity and can be
applied in human or veterinary medicine.